Late-Life Alcohol Exposure Does Not Exacerbate Age-Dependent Reductions in Mouse Spatial Memory and Brain TFEB Activity.
Late-Life Alcohol Exposure Does Not Exacerbate Age-Dependent Reductions in Mouse Spatial Memory and Brain TFEB Activity.
复制标题
晚年接触酒精不会加剧小鼠空间记忆和大脑 TFEB 活动的年龄依赖性下降。
DOI：
10.1101/2024.02.23.581774
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Swerdlow,Russell
中科院分区：
文献类型：
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作者：
Chen,Hao;Hinz,Kaitlyn;Zhang,Chen;Rodriguez,Yssa;Williams,ShaNeisha;Niu,Mengwei;Ma,Xiaowen;Chao,Xiaojuan;Frazier,AlexandriaL;McCarson,KennethE;Wang,Xiaowan;Peng,Zheyun;Liu,Wanqing;Ni,Hong-Min;Zhang,Jianhua;Swerdlow,Russell
人们认为饮酒会影响阿尔茨海默病（AD）的风险，但其作用机制尚不清楚。酒精- ad连接的潜在介质是自噬，这是一种维持细胞器和蛋白质稳态的降解途径。自噬是通过转录因子EB （TFEB）的活性来调节的，转录因子EB促进溶酶体和自噬相关基因的表达。本研究的目的是探讨慢性饮酒是否会加剧脑中tfeb介导的溶酶体生物发生的年龄相关下降，并加剧与衰老相关的认知能力下降。为了探索酒精对脑TFEB和自噬的影响，我们将幼龄（3月龄）和老年（23月龄）小鼠暴露于两种酒精喂养模式下，并评估生化、转录组、组织学和行为终点。在年轻小鼠中，酒精降低了海马核TFEB染色，但增加了SQSTM1/p62、LC3-II、泛素化蛋白和磷酸化的Tau。老年小鼠的海马TFEB活性低于年轻小鼠，高狂欢酒精喂养不会加重与年龄相关的TFEB活性降低。Morris Water和Barnes Maze空间记忆任务用来表征衰老和慢性酒精暴露的影响（小鼠喂食酒精4周）。老年小鼠在两项测试中均表现出较差的空间记忆获取。酒精喂养轻微损害了幼鼠的空间记忆，但对老年小鼠的空间记忆获取几乎没有影响，甚至略有改善。总之，与饮酒相比，衰老导致大脑自噬通量的减少和空间记忆的损害更大。
Alcohol consumption is believed to affect Alzheimer’s disease (AD) risk, but the contributing mechanisms are not well understood. A potential mediator of the proposed alcohol-AD connection is autophagy, a degradation pathway that maintains organelle and protein homeostasis. Autophagy is regulated through the activity of Transcription factor EB (TFEB), which promotes lysosome and autophagy-related gene expression. The purpose of this study is to explore whether chronic alcohol consumption worsens the age-related decline in TFEB-mediated lysosomal biogenesis in the brain and exacerbates cognitive decline associated with aging. To explore the effect of alcohol on brain TFEB and autophagy, we exposed young (3-month-old) and aged (23-month-old) mice to two alcohol-feeding paradigms and assessed biochemical, transcriptome, histology, and behavioral endpoints. In young mice, alcohol decreased hippocampal nuclear TFEB staining but increased SQSTM1/p62, LC3-II, ubiquitinated proteins, and phosphorylated Tau. Hippocampal TFEB activity was lower in aged mice than it was in young mice, and Gao-binge alcohol feeding did not worsen the age-related reduction in TFEB activity. Morris Water and Barnes Maze spatial memory tasks were used to characterize the effects of aging and chronic alcohol exposure (mice fed alcohol for 4 weeks). The aged mice showed worse spatial memory acquisition in both tests. Alcohol feeding slightly impaired spatial memory in the young mice, but had little effect or even slightly improved spatial memory acquisition in the aged mice. In conclusion, aging produces greater reductions in brain autophagy flux and impairment of spatial memory than alcohol consumption.